This K02 application proposes support essential for my career development as a newly independent researcher in brain imaging of addiction and tobacco smoking. Through a K01 funded by NIDA, I attained considerable expertise in brain imaging of tobacco smokers, with a focus on sex differences. I have demonstrated considerable research productivity as evidenced by my increasing number of peer reviewed publications and current grant funding including being principal investigator on two R01s. This K02 award is vital for providing focused research time and for facilitating my maturation into a fully-independent investigator. My current career goal is to use SPECT and PET imaging to examine brain receptor changes during acute and prolonged abstinence from tobacco smoking and to determine biomarkers that may modulate these receptor changes and thus impact tobacco smoking cessation efforts. Included in the proposal is a rigorous 5-year career development training plan that fills important gaps and complements my current expertise in SPECT/PET neuroreceptor imaging. Specifically, I plan to broaden my knowledge in the three areas of genetics, cognition and fMRI, so that I can integrate them in my research on tobacco smoking and addiction in order to have a greater impact on future treatment. Intensive training is provided by an integrated curriculum of intramural coursework, extramural short courses, three individualized preceptorships, interactive symposia, and research-related organizational meetings. A primary NIDA funded research study (R01) is included that examines genetic influences on nicotinic acetylcholine receptor availability in habitual tobacco smokers and nonsmokers. We have previously demonstrated using [123I]5-IA-85380 and SPECT brain imaging that beta2-subunit containing nicotinic acetylcholine receptors (beta2-nAChRs) are higher (26-36%) in the striatum, and throughout the cerebral cortex and cerebellum in tobacco smokers versus nonsmokers and that it takes up to 6-12 of abstinence for these receptors to return to control levels. The findings from the latter study were heterogeneous, with some subjects showing decreases of up to 17% over abstinence and others showing minimal change, e.g., 4%. The goal of the current study is to determine whether this individual variability in beta-nAChR availability during acute and prolonged abstinence is genetically mediated. In the present proposal, we aim to validate this hypothesis through the following specific aims: 1) to determine if beta2-nAChR availability is genetically determined in European-American (EA) never smokers, 2) to determine if the adaptive increase in beta2-nAChR availability in EA smokers is genetically determined and 3) to determine if the change in beta2-nAChR availability over the first 6-8 weeks of abstinence in EA smokers from Aim 2 is genetically determined. The focus is on 2 genes that have been associated with nicotine dependence, the CHRNA4 and ANKK1. The findings from these studies may provide definitive genetic and neurochemical evidence that will allow in future studies for smokers to be stratified and tested for responses to various smoking cessation treatments. PUBLIC HEALTH RELEVANCE: Smoking is the leading known cause of preventable death, yet 25% of the American population continues to smoke. The nicotinic acetylcholine receptor (nAChR) is a critical neurochemical substrate involved in the addiction to cigarette smoking. These studies will define the genes and brain chemicals that may contribute to individual differences in tobacco smoking and will help to design treatment studies that will ultimately help tailor smoking cessation treatments.